The SOST gene encodes a 24 KD protein called sclerostin that has been classified as a member of the DAN family of cysteine knot containing glycoproteins based on sequence similarity (Avasian-Kretchmer (2004) Mol. Endocrinol. 8(1):1-12). Sclerostin is a negative regulator of bone formation that inhibits osteoblast proliferation as well as differentiation and suppresses mineralization of osteoblastic cells in vitro (Poole et al. (2005) FASEB J. 19:1836-38; Winkler et al. (2005) J. Biol. Chem. 280(4): 2498-2502).
Sclerostin is an inhibitor of the canonical Wnt signaling pathway. It binds to LRP4, LRP5 and/or LRP6 receptors leading to stabilization of β-catenin leading to regulation of gene transcription through transcription regulators including lymphoid enhancing factor-1 (LEF) and T cell factors (TCF). Sclerostin inhibition allows signaling through the Wnt pathway resulting in bone formation (van Bezooijen et al. (2007) J. Bone Min. Res. 22(1):19-28).
An increase in canonical Wnt signaling results in increased bone mass (Li et al. (2005) J. Biol. Chem. 280(20):19883-7; Semenov et al. (2005) J. Biol. Chem. 280(29):26770-775). Loss of function mutants in LRP5 lead to the low bone mass phenotype seen in osteoporosis-pseudoglioma syndrome in humans and LRP5 KO mice demonstrate phenotypes similar to those seen in these patients (Balemans et al. (2008) Calcif. Tissue Int. 82:445-53). Two human mutations of the SOST gene have been identified that lead to Sclerosteosis and Van Buchem's disease, both of which result in a high bone mass phenotype (Brunkow et al. (2001) Am. J. Hum. Genet. 68:577-89; Balemans et al. (2001) Hum Mol Genet. 10:537-43). Additionally, sclerostin KO mice demonstrate a high bone mass phenotype while sclerostin over—producing Tg mice have a low bone mass phenotype (Li et al. (2008) J. Bone and Min. Res. 23(6):860-9).
UCB Celltech (formerly Celltech), in collaboration with AMGEN, is developing a sclerostin neutralizing mAb for the treatment of osteoporosis and fracture healing. Phase I clinical trials have been completed. A Phase II trial has been completed in osteoporosis and Phase III trials have been initiated. Multiple Phase II trials are ongoing for the treatment of fracture healing. The pathogenic role of TNF in arthritis is well established as TNF-α antagonists reduce inflammation and limit progression of cartilage damage and bone erosion in human disease (van den Berg (2001) Arthritis Res. 3:18-26). Although TNF antagonists have revolutionized RA therapy, a significant portion of patients do not respond adequately to these drugs. Preclinical studies with TNF-α and SOST point to both independent and overlapping roles in arthritis pathophysiology. Whereas sclerostin or TNF-α inhibition alone exert only modest effects on proinflammatory gene expression, the combination of SOST inhibition with TNF-α inhibition leads to strong synergistic responses. In particular, the combination of inhibiting sclerostin and TNF-α has the potential to both block inflammation and promote bone healing providing greater clinical benefit to patients.
Although a variety of antibodies to sclerostin have been described since the discovery of this critical proinflammatory cytokine, there remains a need for improved antibodies that can effectively mediate or neutralize the activity of sclerostin during an inflammatory response or autoimmune disorder, while protecting or restoring bone mineral density, bone volume and bone strength.